Regulation of food intake and energy expenditure is crucial in maintaining a stable body weight. Excessive energy intake leads to obesity, which is a leading risk factor in many diseases including diabetes and hypertensin. Neuropeptides in the hypothalamus play a critical role in regulating energy balance. A detailed knowledge of hypothalamic peptides and their receptors in controlling feeding, satiety and energy expenditure is key in understanding the causes of obesity and related disorders. Urocortin 3 (Ucn 3) is a new neuropeptide identified in rodents and humans with strong central appetite suppressive effect. Ucn 3 is expressed at high levels in discrete brain areas including the hypothalamus. Ucn 3-expressing neurons heavily innervate the ventromedial hypothalamus (VMH). The receptor for Ucn 3, the type 2 CRF receptor (CRFR2), is highly expressed in the VMH and its expression is regulated by the energy status of the animals. Importantly, direct injection of Ucn 3 into the VMH suppresses food intake, elevates blood glucose levels and activates anorectic POMC neurons in the arcuate nucleus of the hypothalamus. The VMH has been recognized as a satiety center and for its ability to sense blood glucose levels, yet the mechanism by which this brain area regulates feeding and blood glucose is unknown. Thus, we hypothesize that Ucn 3 and its receptor is a critical molecular mediator in the VMH to regulate energy homeostasis. The major objectives of this project are to (1) identify the neurocircuits that mediate the effect of Ucn 3 in the VMH, (2) determine the physiological role of endogenous Ucn 3 and CRFR2 in the VMH in regulating food intake and glucose homeostasis and (3) determine the mechanisms that mediate the effect of Ucn 3 in the VMH.The project will first utilize a novel molecular tracing technique combined with functional anatomy to delineate the neural pathways that mediate the effect of Ucn 3 in the VMH followed by electrophysiological and pharmacological approaches to determine the effect of Ucn 3 on the activity of VMH target neurons. The project will then examine if POMC neurons mediate the appetite suppressive effect of Ucn 3. Finally in vivo small interference RNA approach will be used to examine the physiological role of Ucn 3 and its receptor in the VMH in regulating food intake and energy homeostasis. The proposed project will provide a significant insight into mechanisms through which Ucn 3 in the VMH regulates feeding and controls energy homeostasis.